The association between leptin and subclinical cardiovascular disease explained by body fat: Observational and Mendelian randomization analyses.

BACKGROUND AND AIMS: Leptin has been associated with adverse effects on cardiovascular disease, but the effect of confounding by body fat in these associations remains unclear. To investigate associations between leptin and heart function and subclinical cardiovascular disease adjusted for total body fat, and to investigate the causal relation between leptin and cardiovascular disease using Mendelian randomisation. METHODS AND RESULTS: Leptin concentrations, total body fat and diverse measures of subclinical cardiovascular disease were determined in participants of the Netherlands Epidemiology of Obesity study. Linear regression between leptin concentration and measures of heart function, ECG measures, and carotid intima media thickness as a measure of subclinical atherosclerosis was adjusted for potential confounding factors, and additionally including total body fat. We analysed the combined effects of genetic variants from a GWAS on leptin concentrations in publicly-available summary statistics of coronary heart disease GWAS (CARDIoGRAMplusC4D, n = 184,305). As many as 6107 men and women, mean (SD) age 56 (6) years, BMI 26 (4) kg/m2, and median leptin concentration 12.1 µg (IQR: 6.7-22.6) were included. In observational analyses, leptin was weakly associated with heart function and subclinical cardiovascular disease, but these associations attenuated when adjusting for total body fat. A doubling of genetically-determined leptin concentration was associated with an odds ratio of cardiovascular disease of 0.69 (0.37, 1.27). CONCLUSION: Observational associations between leptin and subclinical measures of cardiovascular disease were largely explained by differences in total body fat. Results of analyses of genetically-determined leptin and coronary heart disease risk were inconclusive due to a large confidence interval.

Increasing HDL-C levels with medication: current perspectives.

PURPOSE OF REVIEW: To date, observational studies have repeatedly demonstrated an inverse association between HDL cholesterol (HDL-C) levels and cardiovascular outcomes. Although the efficacy of established HDL-modifying treatment strategies have been examined in multiple large-scale phase III trials, findings from these experimental studies conflict with the hypothesis that HDL-C levels are atheroprotective. In this review, we describe the trial evidence to date, and attempt to place these results in the broader context of recent hypotheses for the association between HDL-C levels and clinical outcomes. RECENT FINDINGS: Both translational and genetic studies are in line with the hypothesis that HDL-C levels do not hold causal importance for cardiovascular risk reduction. In addition to its possible role as a biomarker for other atherogenic lipoproteins, efforts should be made to elucidate HDLs' role in lipoprotein flux, which is increasingly being linked to surrogate outcomes of importance to cardiovascular epidemiology. In the future, it will be of great importance to link this measure of HDL functionality to clinical endpoints. SUMMARY: Although trial evidence does not support an atheroprotective role of overall HDL-C plasma levels, HDL function/lipoprotein flux holds great promise for the development of novel therapeutic approaches.

Assessment of causality between serum gamma-glutamyltransferase and type 2 diabetes mellitus using publicly available data: a Mendelian randomization study.

Background: In observational studies, high levels of gamma-glutamyltransferase (GGT) have been associated with a higher risk of type 2 diabetes mellitus (T2D). We aimed to assess whether this association is causal, using Mendelian randomization. Methods: A Mendelian randomization study was conducted using publicly available data from a genome-wide association study (GWAS) on T2D (12 171 cases of T2D and 56 862 controls), and additionally from GWAS on glycaemic traits ( N = 46 186) and HbA1c ( N = 46 368) in nondiabetic participants. Independent genetic variants (26 in total), identified in the largest GGT GWAS comprising studies of European ancestry, were used as genetic instruments. Inverse-variance weighted and MR-Egger regression analyses were used to estimate the effect of the combined genetic instrumental variables on T2D and glycaemic traits and HbA1c. Results: F-statistics of the 26 genetic instrumental variables, as a measure of instrumental strength, ranged from 23.4 ( ATP8B1 ) to 258.3 ( GGT1 ). Using inverse-variance analyses, we found no evidence of an association between the combined genetic instrumental variables for GGT and the risk of T2D, or glucose-, insulin- or HbA1c-levels. More specifically, a 10% higher genetically determined GGT was not associated with a higher risk of T2D (odds ratio: 0.99; 95% confidence interval: 0.95; 1.02). Results were similar for MR-Egger regression analyses, which did not show evidence for directional pleiotropy. Conclusion: The previously observed association between high levels of serum GGT and T2D in observational studies might not be causal. Likely, results from the observational studies can be explained by reverse causality and/or residual confounding.

Rooted in risk: genetic predisposition for low-density lipoprotein cholesterol level associates with diminished low-density lipoprotein cholesterol response to statin treatment.

AIMS: To utilize previously reported lead SNPs for low-density lipoprotein cholesterol (LDL-c) levels to find additional loci of importance to statin response, and examine whether genetic predisposition to LDL-c levels associates with differential statin response. METHODS: We investigated effects on statin response of 59 LDL-c SNPs, by combining summary level statistics from the Global Lipids Genetics and Genomic Investigation of Statin Therapy consortia. RESULTS: Lead SNPs for APOE, SORT1 and NPC1L1 were associated with a decreased LDL-c response to statin treatment, as was overall genetic predisposition for increased LDL-c levels as quantified with 59 SNPs, with a 5.4% smaller statin response per standard deviation increase in genetically raised LDL-c levels. CONCLUSION: Genetic predisposition for increased LDL-c level may decrease efficacy of statin therapy.